tbuckley/cabot-search huggingface dataset:
Abstract 2017: A liquid biopsy approach to gastric cancer reveals a signature reflective of epithelial to mesenchymal transition
Authors: Ali H. Abdel Sater, Yihui Chen, Johannes F. Fahrmann, Ehsan Irajizad, Yining Cai, Fuchung Hsiao, Jody V. Vykoukal, Hiroyuki Katayama, Ricardo A. Léon-Letelier, Rongzhang Dou, Edwin J. Ostrin, Melissa Pizzi, Kohei Yamashita, Matheus Sewastjanow Da Silva, Shumei Song, Jaffer Ajani, Samir Hanash
Journal: Cancer Research (2023)

Abstract Comprehensive proteomic profiling of plasmas collected before and after neo-adjuvant treatment for gastric cancer (GC) yielded 522 proteins exhibiting higher pre-treatment levels compared to healthy controls and among them, 345 proteins decreased after the treatment. Increased levels of cytoskeleton-related proteins were manifest in the plasmas of GC patients. Cytoskeletal proteins are known to play integral roles in modulating epithelial plasticity by altering mechanical strength and structural design that is critical for cancer cell motility, epithelial to mesenchymal transition (EMT), metastasis, and invasion. Ingenuity Pathway Analysis of highly expressed circulating proteins identified key oncogenic upstream transcriptional regulators and proteins that promote EMT, including KRAS, MYC and TGFB. Additionally, pathways involved in remodeling of epithelial adherens junctions, actin cytoskeleton signaling and VEGF signaling that also play a key role in EMT were upregulated. Additional datasets from proteomic profiling of multiple (N=6) GC cell lines were intersected with GC patient plasma profiles provided supporting evidence of a cancer cell origin of circulating cytoskeletal features. ACTC1, ACTN1, ACTR3, MYH9, TUBA1A, TUBA4A and TLN1 were highly expressed in both conditioned media released from GC cell lines and plasma samples of GC patients. Our findings are indicative of a blood-based signature of cytoskeletal proteins that is reflective of EMT in the context of gastric cancer. Citation Format: Ali H. Abdel Sater, Yihui Chen, Johannes F. Fahrmann, Ehsan Irajizad, Yining Cai, Fuchung Hsiao, Jody V. Vykoukal, Hiroyuki Katayama, Ricardo A. Léon-Letelier, Rongzhang Dou, Edwin J. Ostrin, Melissa Pizzi, Kohei Yamashita, Matheus Sewastjanow Da Silva, Shumei Song, Jaffer Ajani, Samir Hanash. A liquid biopsy approach to gastric cancer reveals a signature reflective of epithelial to mesenchymal transition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2017.
Abstract 3085: Role of amino acid sequences within the N terminal domain in regulating AF1-mediated glucocorticoid receptor activity
Authors: Shagufta H. Khan, Raj Kumar
Journal: Cancer Research (2023)

Abstract The steroid hormone receptors (SHRs) play an important role in many physiological and pathological processes including endocrine cancers. However, the precise mechanisms by which these SHRs pass signals from a hormone to control gene expression remain a central unresolved problem, which has limited SHRs therapeutic utilities in a cell/tissue specific manner. Role of the activation function-1 (AF1) in this process is of immense importance as it provides platforms for interactions of specific co-regulatory proteins, and thereby dictates the final outcome SHR-regulated target gene expression. The AF1 located in the N-terminal domain (NTD) plays a critical role in regulating cell/tissue-specific effects of SHRs. However, the exact mechanism of this action is not known. It has been suggested that cell/tissue-specific activities of SHRs may be due to AF1 conformations and subsequent coactivator interactions. The SHRs’ NTD/AF1 has been reported to exist in an intrinsically disorder conformation and undergoes disorder-order transition through intra- and inter- molecular allosteric regulations. In the study, we tested whether the flanking sequences around AF1 affect glucocorticoid receptor (GR) activity due, in part, to conformational changes in otherwise ID AF1 that can facilitate its interaction with critical coregulatory proteins such as TATA Box-Binding Protein (TBP) and steroid receptor coactivator-1 (SRC-1). Using biophysical techniques, we found that placing AF1 immediately upstream from the DNA binding domain (DBD) results into acquisition of a relatively ordered conformation in GR AF1. Further analyses revealed that removing amino acid sequences (1-76) prior to AF1 or removal of amino acids (263-420) between AF1 and DBD differentially regulates AF1-mediated GR activity. The results from this study may provide a potential mechanism for cell-dependent differing GR activities as well as other SHRs and thereby, our results may provide additional SHR selectivity needed to target cell-tissue specific gene regulations in current endocrine-based therapies. Citation Format: Shagufta H. Khan, Raj Kumar. Role of amino acid sequences within the N terminal domain in regulating AF1-mediated glucocorticoid receptor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3085.
Abstract 6448: Processed, red, and white meat consumption and breast composition in a prospective cohort study of Chilean girls
Authors: Claire E. Kim, Audrey J. Gaskins, Camila Corvalan, Ana Pereira, John Shepherd, Karin B. Michels
Journal: Cancer Research (2023)

Abstract Meat consumption has been associated with risk of breast cancer. However, the association between different types of meat (processed and unprocessed red, and white) intake during childhood and breast density has not been explored. This prospective study included 290 Chilean girls from the Growth and Obesity Cohort Study. Diet was assessed every 6 months with a 24-hour recall. Dual-energy X-ray absorptiometry was used to assess breast density (absolute fibroglandular volume (FGV)) and percent breast density (FGV/total breast volume, %FGV) at Tanner Breast Staging 4 (B4). Multivariable linear regression models were adjusted for total calorie intake, age at B4, sugar sweetened beverage intake, vegetable intake, TV watching after school, highest maternal education level, BMI z-score, and height. Substitution analysis was assessed using white meat in replacement of processed and unprocessed red meat. There was no association between total, processed and unprocessed red, or white meat intake and %FGV and absolute FGV. In the estimated substitution analyses, we observed a slightly lower breast density when processed or unprocessed red meat was replaced with white meat; however, effect estimates were modest and imprecise. For example, substituting 1 serving of unprocessed white meat for 1 serving of processed or unprocessed red meat was associated -4.1 cm3 (95% CI -10.3, 2.2) and -4.5 cm3 (95% CI -10.3, 1.3) lower absolute FGV, respectively. In this cohort of Chilean girls, there was little association between total or specific types of meat intake and breast density. Substitution analysis of different types of meat and average breast density at Tanner stage 4 Beta coefficient Confidence interval P value Absolute FGV (cm3) Substituting 1 serving of unprocessed white meat for 1 serving of unprocessed red meat -4.1 (-10.3, 2.2) 0.21 Substituting 1 serving of unprocessed white meat for 1 serving of processed red meat -4.5 (-10.3, 1.3) 0.13 Percentage FGV (%) Substituting 1 serving of unprocessed white meat for 1 serving of unprocessed red meat -2.5 (-5.9, 0.8) 0.14 Substituting 1 serving of unprocessed white meat for 1 serving of processed red meat -2.8 (-5.8, 0.3) 0.08 Citation Format: Claire E. Kim, Audrey J. Gaskins, Camila Corvalan, Ana Pereira, John Shepherd, Karin B. Michels. Processed, red, and white meat consumption and breast composition in a prospective cohort study of Chilean girls [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6448.
Abstract 5379: Deep learning enables label-free tracking of heterogeneous subpopulations
Authors: Tyler Jost, Andrea Gardner, Amy Brock
Journal: Cancer Research (2023)

Abstract Observing and quantifying the proliferation of subpopulations in cancer is key to understanding how heterogeneous groups of cells interact and respond to therapy, their environment, and each other. Prior research has demonstrated that cell-state properties such as metastatic potential and genotype perturbation are encoded in cellular morphology and can be identified with various machine-learning approaches. This encoding spans multiple imaging modalities such as brightfield, phase contrast, and stained whole-slide images, and phenotype prediction can be accomplished using both classical and deep machine learning methods. Here we show that not only do these prediction capabilities extend to transcriptomic subpopulations, but that they can be used to track these populations in high throughput longitudinal live-cell imaging experiments. Using single-cell RNA sequencing, we observed that, among untreated MDA-MB-231 triple negative breast cancer cells, there exist two transcriptomically distinct populations of cells. Using fluorescence-activated cell sorting based on the differentially expressed surface marker ESAM, we isolated these subpopulations and fluorescently labeled them with mCherry or GFP depending on their transcriptomic cluster. Cells were then grown in monoculture or coculture and imaged every 4 hours at 20x resolution. To identify the associated transcriptomic cluster, we trained an instance segmentation algorithm, Mask R-CNN, to both segment and classify cells. We find that, despite being derived from the same cell line, these phenotypes can be predicted using phase contrast images alone. These results demonstrate that cellular phenotypes manifested by distinctive RNA expression signatures can now be surveilled in a high-throughput manner across multiple samples and conditions without further RNA sequencing or biomarker labeling. We anticipate that this methodology of high throughput tracking will be applicable to other heterogeneous subpopulations, such as isolated therapy-resistant or sensitive cells. Tracking transcriptomically distinct populations using only high-throughput imaging will increase the granularity of population analysis and enable more rapid assessment of cancer cell evolutionary dynamics. Citation Format: Tyler Jost, Andrea Gardner, Amy Brock. Deep learning enables label-free tracking of heterogeneous subpopulations. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5379.
Abstract 6298: A novel topoisomerase I inhibitor based anti-ICAM-1 antibody drug conjugate for the treatment of hematologic malignancies and solid tumors
Authors: Oi Kwan Wong, David Jackson, Lei Shi, Qi Fei, Xiaocheng Chen, Leonard Post
Journal: Cancer Research (2023)

Abstract Intercellular Cell Adhesion Molecule 1 (ICAM-1, CD54) is a type I transmembrane protein and a member of the immunoglobulin superfamily. ICAM-1 is involved in many key processes such as cell-cell interactions, signal transduction and leukocytes trans-endothelial migration. ICAM-1 is constitutively present at low levels on healthy tissues but highly expressed in some lymphoma, myeloma and some types of solid tumors including melanoma, non-small cell lung cancers and liver cancers. Previous attempt to target ICAM-1 with a monoclonal antibody bersanlimab (BI505, BioInvent) showed that it was well-tolerated but with limited clinical efficacy. To improve the effectiveness of targeting ICAM-1, we developed a novel ICAM-1 antibody drug conjugate (ADC). The ICAM-1 ADC is comprised of a humanized anti-ICAM-1 hIgG1 antibody conjugated to a novel topoisomerase I inhibitor through a cleavable linker at a drug-to-antibody ratio (DAR) of about 8. The antibody moiety of the ADC targets a unique epitope on ICAM-1 which is far from its ligand binding domain. Potent in vitro cytotoxicity of ICAM-1 ADC, with nanomolar to sub-nanomolar EC50, was observed on a panel of hematologic and solid tumor cell lines. In preclinical studies, one or two doses of ICAM-1 ADC at 5-6 mg/kg were generally sufficient to induce tumor regression in multiple cell line-derived xenograft models, including those of lung and liver cancers. In all models tested so far, the novel topoisomerase I inhibitor conjugated ICAM-1 ADC is at least as efficacious as the same ICAM-1 antibody conjugated to the benchmark topoisomerase I inhibitor linker payload deruxtecan (ICAM-1-DXd). Furthermore, in a repeat dose exploratory non-human primate safety study, the benchmark conjugate ICAM-1-DXd (DAR 8) was well-tolerated at 41 mg/kg, the highest dose tested. In conclusion, ICAM-1 is an attractive target for topoisomerase I inhibitor based ADC and warrants further investigation. Citation Format: Oi Kwan Wong, David Jackson, Lei Shi, Qi Fei, Xiaocheng Chen, Leonard Post. A novel topoisomerase I inhibitor based anti-ICAM-1 antibody drug conjugate for the treatment of hematologic malignancies and solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6298.
Abstract 6435: BCG008, a human Siglec-15 blocking antibody, displays potent anti-tumor activity in Siglec-15-humanized mice
Authors: Yongfei Yang, Aidong Qu, Fengping Yao, Pan Song, Hongyuan Liang, Maopeng Tian, Fang Yang, Zhaoxue Yu, Xu Zhou, Xiuling Li
Journal: Cancer Research (2023)

Abstract Sialic acid-binding Ig-like lectin 15, or Siglec-15, is identified as a critical immune suppressor. Siglec-15 expression is normally limited to certain myeloid cells, but it can be upregulated in a variety of tumors and on tumor-infiltrating myeloid cells. Siglec-15 significantly inhibits antigen-specific T cell responses both in vitro and in vivo. Conversely, genetic ablation of Siglec-15 promotes anti-tumor responses. Therefore, a Siglec-15-targeting blocking antibody could represent a novel class of anti-tumor immunotherapy. BCG008, a fully human monoclonal antibody antagonist of Siglec-15, was generated from RenMab™ mice, which contain the entire human immunoglobulin variable domain. Compared to a reference Siglec-15 blocking antibody (5G12), BCG008 exhibited higher affinity for human and cynomolgus monkey Siglec-15 and targeted distinct binding epitopes. In in vitro studies, BCG008 significantly abrogated Siglec-15-mediated T cell suppression in a dose-dependent manner, as measured by CD4+ and CD8+ T cell proliferation. Subsequently, the efficacy and safety of BCG008 was evaluated in syngeneic tumor models in Siglec15-humanized mice. BCG008 monotherapy significantly inhibited tumor growth, and the effect of the tumor inhibition was potentiated when administered in combination with other immune-checkpoint inhibitors, including anti-PD-L1 antibodies. In safety evaluation, BCG008 was well-tolerated in the tumor-bearing mice; no adverse effects were observed even at high doses (e.g. 30 mg/kg). Taken together, these results demonstrate that BCG008 is a novel anti-human Siglec-15 blocking antibody with favorable efficacy and safety profiles that can provide potential benefits for future cancer immunotherapy. Citation Format: Yongfei Yang, Aidong Qu, Fengping Yao, Pan Song, Hongyuan Liang, Maopeng Tian, Fang Yang, Zhaoxue Yu, Xu Zhou, Xiuling Li. BCG008, a human Siglec-15 blocking antibody, displays potent anti-tumor activity in Siglec-15-humanized mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6435.
Abstract 4886: PARP-1 and γ-GCS inhibitors enhance platinum sensitivity in ovarian cancer
Authors: Luxmi Devi, Ashok Sharma, Lalit Kumar
Journal: Cancer Research (2023)

Abstract Background: Ovarian cancer is the most important cause of gynaecological cancer-related mortality globally. Approximately 80% of patients are diagnosed with advanced stage (FIGO stage III-IV) of ovarian cancer. The standard treatment approach for advanced EOC is primary debulking surgery followed by adjuvant chemotherapy using taxanes plus platinum. Resistance to platinum based chemo remains a key reason for treatment failure in advanced epithelial ovarian cancer (EOC). Therapeutic efficacy of Poly [ADP-ribose] polymerase 1 (PARP1) and Gamma-glutamyl cysteine Synthetase (γ-GCS)inhibitors in ovarian cancer remains undefined, either as a single agent or in combination with cisplatin. Material and Methods: We determined the combined effect of PJ34 (PARP1 inhibitor) and BSO (Buthionine-sulfoximine- (γ-GCS inhibitor) with cisplatin in ovarian cancer cell lines (OVSAHO, KURAMOCHI, and IGROV1) by MTT assay. PARP1 and GCS levels were analyzed by western blotting. We employed flow cytometry for cell cycle analysis as well as for apoptosis studies. Analysis was done using Graph Pad Prism-6. Results were considered to be statistically significant when p value was &amp;lt; 0.05. Results and Conclusion: Combination of cisplatin with PJ34 and BSO augmented cisplatin toxicity in vitro by decreasing cell proliferation and enhancing cell cycle block and cell death when compared with either single agent. A significant cell death (p= &amp;lt;0.05) was observed with the combination of cisplatin, BSO and PJ34. Conclusion: In conclusion, our study provide experimental evidence on the combined effect of PARP-1 and GCS inhibition on CDDP-induced cytotoxicity in epithelial ovarian cancer cells. We propose that PARP-1and BSO inhibitors can be combined with cytotoxic chemotherapeutic agents such as CDDP to enhance the cytotoxicity of chemotherapeutic agents and inhibit key signalling pathways involved in cell proliferation and apoptosis. Future comprehensive studies are needed to demonstrate further validation of above combination. Keywords: Ovarian Cancer, cisplatin, PARP-1, PJ34, γ -GCS, β-actin, Glutathione. Abbreviations: Epithelial Ovarian Cancer (EOC), cisplatin (CDDP), Glutathione (GSH), Gamma Glutamyl Cysteine Synthetase (γ-GCS), Poly (ADP ribosyl) polymerase-1 (PARP1), Nucleotide excision repair (NER),homologous repair (HR), Enzyme-linked immunosorbent assay (ELISA), Buthionine Sulfoximine (BSO), Quantitative Polymerase Chain Reaction (qPCR), Peripheral Blood (PB). Propidium Iodide(PI). Citation Format: Luxmi Devi, Ashok Sharma, Lalit Kumar. PARP-1 and γ-GCS inhibitors enhance platinum sensitivity in ovarian cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4886.
Abstract 1714: <i>CRACD/KIAA1211</i> loss drives cell plasticity and immune evasion of small cell lung cancer
Authors: Shengzhe Zhang, Kee-Bum Kim, Yuanjian Huang, Dong-Wook Kim, Bongjun Kim, Kyung-Pil Ko, Gengyi Zou, Jie Zhang, Sohee Jun, Nicole A. Kirk, Ye Eun Hwang, Young Ho Ban, Joseph M. Chan, Charles M. Rudin, Kwon-Sik Park, Jae-Il Park
Journal: Cancer Research (2023)

Abstract Small cell lung carcinoma (SCLC) is a lethal neuroendocrine type of lung cancer with limited therapeutic options. Despite recent advances in cancer immunotherapy, its efficacy is limited to a small subset of SCLC patient tumors. The molecular origin of the refractoriness to immunotherapy remains elusive. CRACD (Capping protein inhibiting regulator of actin dynamics; KIAA1211/CRAD) gene is frequently mutated and transcriptionally downregulated in SCLC. Cracd knockout (KO) causes the transformation of preneoplastic neuroendocrine cells and significantly accelerates SCLC development in a mouse model initiated by the loss of Rb1, Trp53, and Rbl2 in the lung epithelium. Cracd KO induces tumor cell plasticity generating deregulated cell lineage trajectories of SCLC tumors. Strikingly, Cracd KO SCLC tumors display the complete loss of CD8+ T cells due to epigenetic suppression of the MHC-I pathway. Furthermore, single-cell transcriptomic analyses of SCLC patient samples classified SCLC by concurrent features: CRACD inactivation and tumor antigen presentation impairment. This study suggests CRACD as a tumor suppressor of SCLC that regulates proliferation and immune recognition of cells, providing novel insight into the mechanism of SCLC evading immune surveillance. Citation Format: Shengzhe Zhang, Kee-Bum Kim, Yuanjian Huang, Dong-Wook Kim, Bongjun Kim, Kyung-Pil Ko, Gengyi Zou, Jie Zhang, Sohee Jun, Nicole A. Kirk, Ye Eun Hwang, Young Ho Ban, Joseph M. Chan, Charles M. Rudin, Kwon-Sik Park, Jae-Il Park. CRACD/KIAA1211 loss drives cell plasticity and immune evasion of small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1714.
Abstract 1109: Effects of radiation therapy on the hardness of enamel and dentin
Authors: Rachel Kulchar, Florin Eggmann, Celine Mina, Steven Szewczyk, Kakiuchi Yusuke, Jie Deng, Francis Mante
Journal: Cancer Research (2023)

Abstract Introduction: Radiation therapy is often used as the main or adjunctive treatment for cancer in the oral cavity. Unfortunately, prolonged exposure to radiation has adverse effects on tissues of the oral cavity, including a decrease in the hardness of dentin. Consequently, patients who receive radiation therapy are susceptible to tooth sensitivity and caries. Fluoride treatments have proven to be effective in restoring the hardness of dentin as it remineralizes the tooth. The aim of this study was to determine the optimal fluoride treatment for restoring the hardness of irradiated teeth. Methods: 100 teeth were extracted, cleaned, and mounted in acrylic resin. The teeth were ground and polished to expose the dentin and enamel. The initial Knoop hardness of the teeth was measured and split equally among five groups and treated as follows: (1) sodium fluoride varnish (SF), (2) MI varnish (MI), (3) silver diamine fluoride and potassium iodide (SDFKI), (4) silver diamine fluoride (SDF), and (5) no treatment (NT). All groups were subjected to 2 grays of daily radiation treatment for 6 weeks. The hardness of the dentin was measured immediately following radiation. Afterwards, the 5 treatments were applied weekly for 6 weeks. Hardness was measured 1 week after each treatment. Kruskal-Wallis one way analysis of variance on ranks was used to compare the different groups. Results: After 6 weeks of fluoride treatment, there was a significant difference (p = 0.013) between the hardness of the irradiated enamel, with Group 4 resulting in the largest median measurement (263.4). Similarly, 5 weeks of fluoride application resulted in a mean hardness of dentin that was 15.8%, 13.6%, 16.2%, and 19.4% higher than the control for groups 1, 2, 3, and 4, respectively. Again, Group 4 had the highest hardness measurement. Conclusions: Radiation therapy decreases the hardness of enamel and dentin. SDF treatment resulted in the highest hardness for both irradiated dentin and enamel, suggesting that SDF is promising as a fluoride treatment for those undergoing radiation therapy for oral cancer. Citation Format: Rachel Kulchar, Florin Eggmann, Celine Mina, Steven Szewczyk, Kakiuchi Yusuke, Jie Deng, Francis Mante. Effects of radiation therapy on the hardness of enamel and dentin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1109.